Understanding the development of adolescent health gene-environment interactions on the etiology of alcohol use, substance use, and aggressive behavior risk behaviors requires examination of both genetic and environmental variables and their interactions. This study proposes to test interactions between genetic markers from five carefully selected regions - the serotonin transporter gene (SLC6A4), the monoamine oxidase A gene (MAOA), the catechol-O-methyltransferase gene (COMT), the type 4 dopamine receptor gene (DRD4), and a series of tag SNPs in a high LD region on chromosome 15 overlapping three nicotine receptors (CHRNA5-CHRNA3-CHRNB5) and theoretically-based contextual variables (stress, models of health risk behaviors, and social controls) from four key social contexts (family, peer, school, and neighborhood) on trajectories of adolescent tobacco use, alcohol misuse, illicit drug use, and aggression (in general and against peers and dates). Aim 1 is to determine if associations between these genetic markers and trajectories of health risk behaviors are moderated by theoretically-based contextual variables in the directions hypothesized. The study is intended also to illuminate which theoretical constructs (aim 2) and social contexts (aim 3) are most important in moderating associations between genetic markers and trajectories of risk behaviors, and which health risk behaviors are most influenced by gene-by-environment interactions (aim 4). Data are already available from a seven- wave prospective cohort study (n = 4000) for measuring the health risk behaviors and contextual variables from ages 11 through 19. In that study innovative measurement techniques were used including social network analyses to measure the peer and school context and U.S. Census data at the block group level (n = 58) and adolescent and parent self-reports to measure neighborhood context. For the proposed study, whole blood will be collected from the now young adults and genotyped. Those data will be merged with data from the prospective study to address the four specific aims. The study features several conceptual extensions from prior studies including assessing the influence of interactions on trajectories rather than point estimates of adolescent health risk behaviors, allowing for an examination of how the influence of gene-by-environment interactions on health risk behaviors change across adolescence, use of theoretically- based contextual moderators, and examination of moderators from contexts besides the predominately studied family context. The proposed study also addresses notable methodological limitations of candidate gene-by- environment studies by having strong measures of the contextual variables, selecting a limited number of empirically justified candidate genes to study, using a prospective design, incorporating a K-fold cross- validation procedure, controlling for ancestral heritage, and having sufficient power for detecting moderation, even when stratifying by gender. Understanding the conditions under which the associations between non- malleable genotypes are exacerbated or neutralized is crucial for developing effective public health and individualized programs to promote healthy adolescent development. PUBLIC HEALTH RELEVANCE: Genetic by Context Influence on Trajectories of Adolescent Health Risk Behaviors Project Summary - Relevance Tobacco use, alcohol misuse, illicit drug use, and aggression are significant public health problems. The study will contribute toward understanding the conditions under which the associations between non-malleable genotypes and these health risk behaviors are exacerbated or neutralized and this understanding is crucial for developing effective public health and individualized programs for preventing these public health problems and for promoting healthy adolescent development.